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FIGURE 14 Discharges induced by bilateral application of 2.5ml of the 200mg/ml pentylenetetrazol (PTZ) solution on the sensorimotor cortex in a freely moving adult Wistar rat. Individual discharges (sharp waves) are well synchronized between both frontal areas; transfer to the occipital areas (especially left one) is incomplete. RF, right frontal (sensorimotor) cortex; RO, right occipital (visual) cortex; LF, left frontal cortex; LO, left occipital cortex.

FIGURE 14 Discharges induced by bilateral application of 2.5ml of the 200mg/ml pentylenetetrazol (PTZ) solution on the sensorimotor cortex in a freely moving adult Wistar rat. Individual discharges (sharp waves) are well synchronized between both frontal areas; transfer to the occipital areas (especially left one) is incomplete. RF, right frontal (sensorimotor) cortex; RO, right occipital (visual) cortex; LF, left frontal cortex; LO, left occipital cortex.

induce spreading depression (for review, see Somjen, 2001). This feature may account for some of its paradoxical anticonvulsant effects when it is applied focally (Turski et al., 1987).

Insights into Human Disorders

Mechanisms of action for these drugs were mentioned during the description of their systemic use (see preceding). All these models represent models of focal seizures with possible secondary generalization. According to the localization of the initial injection site or the preferential activity of the drug, the model can be of focal motor seizures with elementary clonic motor signs or focal seizures with typical automatisms (Engel, 2001). Focal administration of convul-sant drugs may serve as a model for screening antiepileptic drugs potentially useful in treatment of focal-onset seizures.

Antibiotics (Penicillins and Cephalosporins)

Methods of Generation

Epileptogenic effects of antibiotic drugs were first described in monkeys and later in humans (Johnson et al. 1946; Walker and Johnson, 1945; Walker et al., 1945). Locally administered penicillin (Velisek and Moshe, 2000a) produces an epileptic focus in many other species, including rats and cats. The potency of antibiotic drugs to induce epileptiform discharges has been studied repeatedly both in vivo (Gutnick et al., 1976) and in vitro (Grondahl and Lang-moen, 1993). After application on the cortex, the convulsant potency is the following: benzyl penicillin (threshold concentration ~25 mmol/L), phenoxymethylpenicillin (~100mmol/L), oxacilin (~150mmol/L), methicillin (~150mmol/L), and ampicillin (~175mmol/L) (Gutnick et al., 1976). Sodium and potassium salts of penicillins are preferred for application because their solubility is superior to the antibiotic bases. Cephalosporins, especially the first generation, have also substantial epileptogenic potency if applied focally (Kamei et al., 1983); for review see (Velisek and Moshe, 2000b). Some epileptogenic antibiotic drugs the cross blood barrier, although in limited amounts. Therefore, it is possible to induce seizures by systemic injections of high doses of some penicillins or cephalosporins. Cats are more sensitive to systemic antibiotics than rats or mice (Chen et al., 1986; Eng et al., 1989; Gloor and Testa, 1974; Nistico et al., 1978; Yu et al., 1984).

Defining Features

Seizures depend on the exact localization of the focus. Interictal focal activity is usually accompanied with isolated twitches, while the ictal discharges may be associated with a clonic seizure. The penicillin focus is very localized (Noebels and Pedley, 1977) and the neurons display the paroxysmal depolarizing shift, the hallmark of epileptic neurons in the epileptic focus (Matsumoto and Ajmone-marsan, 1964; Prince, 1968). Neurons around the focus exert substantial inhibitory activity in an attempt to limit the spread of the seizure (Prince and Wilder, 1967).

Limitations

If a high concentration of a potassium salt of the antibiotic drug is directly applied onto the cortex, spreading depression may develop (for review, see Somjen, 2001), masking thus the onset of discharges and interfering with the experiment. Therefore sodium salts are preferred, if they are available.

Insights into Human Disorders

Low doses of penicillin selectively block GABAa mediated inhibitory postsynaptic potentials as a result of their GABAA receptor antagonism (Dingledine and Gjerstad, 1980; Wong and Prince, 1979). Higher doses may have additional nonspecific effects (Ayala et al., 1970). Focally administered epileptogenic antibiotics produce a model of focal seizures with initial symptoms that depend on the exact localization (Engel, 2001). After generalization of the electrical seizure activity from the focus, clonic seizures may occur.

Tetanus Toxin

Methods of Generation

Focal administration of tetanus toxin (Griffin and Oyler, 2000) introduced by Mellanby and colleagues (Mellanby et al., 1977) can induce seizures in both mice and rats. Hip-pocampal localization of tetanus toxin injection is used to produce recurrent seizures (see Fisher, 1989). After the infusion of 4 to 5ng in 1 ml of phosphate buffer (Finnerty and Jefferys, 2002), the seizures occur within a day and recur chronically over weeks (see Chapter 33 for further details).

Defining Features

In rats a seizure usually begins with behavioral arrest, followed by myoclonic twitches of forelimbs and sometimes with tonic-clonic seizures. Seizures may be quite frequent (up to 100 per day, returning for a month). EEG shows fast spikes or spike and waves (3-20 Hz) (Jefferys and Williams, 1987).

Limitations

There is limited neuropathology and temporal limitation for recurrent seizures.

Insights into Human Disorders

After focal administration, tetanus toxin is picked up by nerve endings and interferes with synaptic vesicular release.

As per localization of the focus in the hippocampus, this is a model of focal seizures with typical automatisms (Engel, 2001) with further generalization. This model is used with advantage in both immature (Anderson et al., 1999; Rashid et al., 1999; Smith et al., 1998) and adult rats (Jefferys and Williams, 1987) because epileptogenesis develops after initial seizures.

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